title: [Virtual screening of small molecular HIV-1 entry inhibitor NC-2 targeting gp120 and its action mechanism].
abstract: OBJECTIVE
  To screen the HIV-1 entry inhibitors targeting HIV-1 gp120 from the IBS natural product database by virtual screening based on the binding mode of the neutralizing antibody VRC01 with HIV-1 gp120 and investigate the anti-viral activities of the inhibitors and their action mechanisms.
  
  
  METHODS
  The binding interaction of the candidate molecules binding gp120 and changes of the binding free energy were analyzed by MM-PBSA calculation. The anti-HIV-1 activities of the tested compounds were detected by HIV-1 pseudotyped virus, laboratory-adapted HIV-1 and a cell-cell fusion assay. The cytotoxicity of the studied molecules was examined by XTT colorimetric assay. The mechanisms of the anti-viral activities of the candidate molecules were analyzed using enzyme-linked immunosorbent assay.
  
  
  RESULTS
  A total of 19 molecules with distinct reduction of the binding free energy after binding with gp120 were screened from 40000 molecules. Among them, NC-2 showed anti-HIV-1 activities against HIV-1 pseudotyped virus and laboratory-adapted HIV-1, and was capable of blocking HIV-1 envelope-mediated cell-cell fusion. The IC50 of NC-2 for inhibiting HIV-1IIIB and pseudotyped HIV-1JRFL infection were 1.95∓0.44 µmol/L and 10.58∓0.13 µmol/L, respectively. The results of ELISA suggested that NC-2 could inhibit the binding of HIV-1 gp120 to CD4 without blocking the formation of gp41 six-helix bundle in vitro.
  
  
  CONCLUSIONS
  This computer-based virtual screening method can be used to screen HIV-1 entry inhibitors targeting gp120. Using this virtual screening approach combined with anti-viral activity screening, we obtained a potent HIV-1 entry inhibitor NC-2 with novel structure.
authors.affiliation: School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. duanheng1121@ gmail.com
authors.forename: Heng
authors.initials: H
authors.lastname: Duan
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Wang
authors.forename: Deshou
authors.initials: D
authors.lastname: Song
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Chen
authors.forename: Jiayin
authors.initials: J
authors.lastname: Qiu
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Shuwen
authors.initials: S
authors.lastname: Liu
authors.forename: Suiyi
authors.initials: S
authors.lastname: Tan
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001665:Binding Sites; D000080908:Broadly Neutralizing Antibodies; D002459:Cell Fusion; D002460:Cell Line; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D015483:HIV Antibodies / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests
chemical_list: D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000080908:Broadly Neutralizing Antibodies; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C578595:VRC01 monoclonal antibody